Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy

Nat Commun. 2014 May 13;5:3828. doi: 10.1038/ncomms4828.

Abstract

Endosomal protein sorting controls the localization of many physiologically important proteins and is linked to several neurodegenerative diseases. VPS35 is a component of the retromer complex, which mediates endosome-to-Golgi retrieval of membrane proteins such as the cation-independent mannose 6-phosphate receptor. Furthermore, retromer is also required for the endosomal recruitment of the actin nucleation promoting WASH complex. The VPS35 D620N mutation causes a rare form of autosomal-dominant Parkinson's disease (PD). Here we show that this mutant associates poorly with the WASH complex and impairs WASH recruitment to endosomes. Autophagy is impaired in cells expressing PD-mutant VPS35 or lacking WASH. The autophagy defects can be explained, at least in part, by abnormal trafficking of the autophagy protein ATG9A. Thus, the PD-causing D620N mutation in VPS35 restricts WASH complex recruitment to endosomes, and reveals a novel role for the WASH complex in autophagosome formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics*
  • Autophagy-Related Proteins
  • Cell Line, Tumor
  • Endosomes / metabolism*
  • Golgi Apparatus / metabolism*
  • HeLa Cells
  • Humans
  • Membrane Proteins / metabolism
  • Parkinson Disease / genetics*
  • Protein Transport / genetics
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism
  • Wiskott-Aldrich Syndrome Protein Family / metabolism

Substances

  • Atg9a protein, human
  • Autophagy-Related Proteins
  • Membrane Proteins
  • VPS35 protein, human
  • Vesicular Transport Proteins
  • WASF1 protein, human
  • Wiskott-Aldrich Syndrome Protein Family

Supplementary concepts

  • Parkinson Disease, Familial, Type 1